The following Compound (1):
(hereinafter “Compound (1)” or a “compound of formula (1)”) is known as a selective and potent inhibitor of the HCV NS3 serine protease. Compound (1) falls within the scope of the acyclic peptide series of HCV inhibitors disclosed in U.S. Pat. No. 6,323,180 and U.S. Pat. No. 7,514,557; and U.S. Pat. No. 7,585,845. Compound (1) is disclosed specifically as Compound #1055 in U.S. Pat. No. 7,585,845, and as Compound #1008 in U.S. Pat. No. 7,514,557. Compound (1) can be prepared according to the procedures found in the above-cited references, which are herein incorporated by reference in their entirety. Preferred forms of Compound (1) include the crystalline forms, in particular the crystalline sodium salt form, which can be prepared as described in the examples section herein.
Compound (1) may also be known by the following alternate depiction of its chemical structure, which is equivalent to the above-described structure:
wherein B is
L0 is MeO—; L1 is Br; and R2 is

A common problem among protease inhibitors is that these compounds are lipophilic and have low aqueous solubility. Because of the poor aqueous solubility, conventional solid and liquid pharmaceutical preparations containing these inhibitors may not be absorbed by the patient in a satisfactory manner. Of the various factors that can affect the bioavailability of a drug when administered orally, (which include aqueous solubility, drug absorption through the gastrointestinal tract, dosage strength and first pass effect), aqueous solubility is often found to be among the most important factors. Poorly water soluble compounds often exhibit either erratic or incomplete absorption in the digestive tract, and thus produce a less than desirable response.
Compound (1) is zwitterionic and is capable of forming salts with strong acids and bases. Attempts to identify salts of such compound in solid forms, which would substantially improve aqueous solubility and therefore bioavailability, have not been successful. Thus, there is a need in the art for pharmaceutical compositions of Compound (1) having improved bioavailability.
Methods of formulating certain lipophilic macrocyclic compounds into pharmaceutical formulations have been previously reported. For example, Cavanak, U.S. Pat. No. 4,388,307, discloses the preparation of emulsified formulations of commercially available cyclosporins, and Hauer et. al, U.S. Pat. No. 5,342,625, and Meizner et al. WO 93/20833 disclose the preparation of cyclosporin microemulsions and microemulsion pre-concentrates. Komiya et. al, U.S. Pat. No. 5,504,068, further to discloses the preparation of an enhanced topical formulations of cyclosporin.
Examples of “self-emulsifying” formulations of lipophilic compounds include Lipari et al, WO 96/36316, which discloses a self-emulsifying pre-concentrate comprising a lipophilic compound, d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and a lipophilic phase. Gao et al., U.S. Pat. No. 6,121,313 discloses a self-emulsifying formulation of a pyranone protease inhibitor comprising the pyranone compound, a mixture of mono- and di-glycerides, one or more solvents and one or more surfactants, and Gao et al, U.S. Pat. No. 6,231,887 B1 discloses a self-emulsifying formulation of a pyranone protease inhibitor comprising the pyranone compound, an amine, one or more solvents and one or more surfactants. Crison et al. U.S. Pat. No. 5,993,858 discloses a self-microemulsifying excipient formulation which comprises an emulsion including an oil or other lipid material, a surfactant and a hydrophilic co-surfactant.
Patel et al. U.S. Pat. Nos. 6,294,192 and 6,451,339 disclose compositions for delivery of a hydrophobic therapeutic agent comprising a carrier formed from a combination of a hydrophilic surfactant and a hydrophobic surfactant. Aylwin et al. U.S. Pat. No. 6,652,880 discloses a liquid pharmaceutical composition wherein the active is dissolved in a liquid vehicle comprising a glyceride of a long chain fatty acid and a lipophilic surfactant.
A self-emulsifying drug delivery system (SEDDS) has also been developed for certain anti-HCV compounds, as described in U.S. Pat. Nos. 6,828,301 and 7,157,424 and U.S. Patent Application Publication No. 2004/0033959. However, there remains a need in the art for a pharmaceutical formulation of Compound (1) that is sufficiently optimized, stable and bioavailable.